Evidence of accelerated epigenetic aging of breast tissues in patients with breast cancer is driven by CpGs associated with polycomb-related genes

Abstract

Purpose Age is one of the strongest risk factors for the development of breast cancer, however, the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression. Methods Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls). Results The Levine (p = 0.0037) and Yang clocks (p = 0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb-related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb-related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p = 0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration. Conclusions Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb-related genes can be used to assess the risk of developing breast cancer among unaffected individuals.

DNA methylation accelerated age as captured by epigenetic clocks influences breast cancer risk

“…The data sources used by these studies included Komen Breast Tissue Bank ( 26 , 28 ), the prospective cohort Sister Study ( 25 , 27 ), National Cancer Institute Genomic Data Commons ( 24 ), and samples from clinical settings ( 24 ). The study of the Sister Study ( 25 ) had the largest sample sizes of N=2,764.…”

“…A total of 10 different epigenetic clocks were used ( Table 1 ). The Horvath clock was most frequently used appearing in three of the five studies ( 24 – 26 ). The included studies found that DNAm age from the following epigenetic clocks had a statistically significant association with breast cancer: Hannum ( 25 ), Horvath ( 25 ), Levine ( 25 , 26 ), GrimAge ( 25 , 27 ), DNAmAge ( 28 ), and Yang ( 26 ).…”

“…Rozenblit et al. ( 26 ) tested for correlations of DNAm age and chronological age in both cases and controls. For breast tissue (n=84), five of the six clocks used showed significant correlations ranging from the Levine clock r =0.35 to the Lin clock r =0.68.…”

Aging and cancer epigenetics: Where do the paths fork?

“…With regards to the alterations—acceleration or deceleration—observed in the clocks, various associations have been investigated, particularly the aforementioned links with environmental factors and disease (Fransquet et al, 2019 ; Levine et al, 2018 ; Lu et al, 2019 ; Marioni et al, 2015 ; Oblak et al, 2021 ), to ascertain whether the DNAm alterations which occur during these processes could drive the changes observed in the clocks. For instance, a recent study investigating DNAm age acceleration in the non‐tumoral breast tissue of breast cancer patients demonstrated that the observed alteration in the epigenetic clock could be explained by a subset of the clock CpGs that suffer from the well‐known cancer‐associated hypermethylation of Polycomb associated loci (Rozenblit et al, 2022 ). Indeed, clocks have been constructed which partly reflect the DNAm alterations induced by cancer‐related lifestyle factors such as smoking (Lu et al, 2019 ).…”

Editorial: DNA methylation: The aging clock

“…Finally, Liu et al investigate the impact of ethnicity on DNA methylation changes in peripheral blood cells from breast cancer (BC) patients. Age is one of the strongest risk factors for the development of BC, and evidence shows accelerated epigenetic aging in normal breast tissues adjacent to breast tumors in BC patients ( Hofstatter et al, 2018 ; Rozenblit et al, 2022 ). DNA methylation signatures have been identified in the white blood cells as potential biomarkers for BC.…”